Chronic severe asthma affects only a subsegment of patients with asthma and is characterized, in part, by persistent airflow obstruction and symptoms despite ongoing treatment. Because of the severity of their disease, this population of asthmatic patients has the greatest morbidity and health care costs. At present, the mechanisms that cause severe asthma are not fully established. The overall goal of this research project is to define the features of severe asthma, identify the mechanisms that lead to this phenotype and discover possible inroads for new and more effective therapies. Based upon existing evidence and preliminary data, it is the hypothesis of this research project that severe asthma is caused, in some patients, by a persistent respiratory infection by viruses (i.e. rhinovirus, respiratory syncytial virus, or adenovirus), Mycoplasma pneumonia, or Chlamydia pneumonia. It is further proposed that these agents infect lower airway epithelium and macrophages to enhance the production of inflammatory cytokines/chemokines (i.e. IL-8) and recruitment of inflammatory cells, particularly neutrophils, to further airway injury and airflow obstruction. To accomplish these goals, subjects with severe asthma (i.e. FEV1 <75% predicted, and ongoing symptoms despite high doses of inhaled corticosteroids) will be recruited along with three groups for comparison: Mild asthma, asthma with airflow obstruction, i.e. FEV, <75% predicted, but reversible to beta agonists, and normals. Measurements of preliminary physiology will be made in these four groups to test the hypothesis that severe asthma is characterized by airway-parenchymal uncoupling. In addition, imaging techniques will be used to correlate determinants of pulmonary physiology with airway structure, by high resolution computerized tomography, and ventilation abnormalities, by magnetic resonance imaging with inhaled hyperpolarized helium. To determine the characteristics of inflammation in peripheral blood, sputum, and lavage fluid, mucosal biopsies will be obtained to assess the hypothesis that neutrophilic inflammation and IL-8 are characteristic features of fixed airway obstruction in severe asthma whereas eosinophilic injury and IL-5 are associated more with reversible airway obstruction. Finally, PCR and immunohistochemistry of lavage fluid and mucosal biopsies will be used to test the hypothesis that severe asthma and fixed airway obstruction with IL-8 and neutrophils are associated with a persistent respiratory infection by respiratory viruses (i.e. adenovirus, influenza, respiratory syncytial virus or rhinovirus), Mycoplasma pneumonia, or Chlamydia pneumonia. It is proposed that these studies will provide new insights into mechanisms of asthma, and particularly severe persistent disease, and potential new approaches to treatment.